3.Cartilage aging/Osteoarthritis (OA)-New investigator. Osteoarthritis (OA) is a common degenerative joint disease characterized by the prosgressive loss of articular cartilage and eventual exposure of underlying bone, causing pain, stiffness, and frequently culminating in total joint disability. OA is more prevalent and more severe among the elderly, and the disease is recognized as the leading cause of long-term disability among people over the age of 60. Inteleukin-1 (IL-1) is proposed to mediate a "final common pathway" of biochemical and morphological changes leading to joint destruction. The overall hypothesis driving this research is that the processing of IL-1alpha precursor and translocation of the two bioactive domains is intimately linked with progression from the early reversible phase of OA to the "point of no return", where damage to the cartilage extracellular matrix is so extensive that repair is no longer possible. IL-1alpha produced by chondrocytes may signal through both paracrine and recently proposed intracellular or "intracrine" signal transduction pathway(s) to activate catabolic processes and repress anabolic ones. Pilot studies are planned to explore this hypothesis. An antiserum to the N-terminal propiece (NTP) of IL-1alpha will be prepared for the study of IL-1 metabolism in OA chondrocytes. Depletion of the proteoglycan aggrecan, which enables cartilage to resist compression under load, is an early event in OA. Increased cartilage deformation may trigger proessing of IL-1alpha precursor. The processing and extracellular transport of IL-1alpha in OA cartilage following mechanical loading will be investigated by immunoblot analysis of cartilage extracts using the antisera to the NTP and the mature cytokine, IL-1alpha processing may be correlated with the progression of OA. Relative steady state levels of IL-1alpha polypeptides in various OA cartilage specimens will be examined to assess whether processing to generate two bioactive domains precedes the transition from reparative to degenerative phase of OA. If these pilot studies are successful, they will justify a thorough exploration of the metabolism and signaling pathways of IL-1alpha with chondrocytes in the context of OA progression.